Positive-sense, single-stranded RNA viruses translate their RNA genome into large polyproteins which are subsequently proteolytically processed to yield the mature viral proteins. Hepatitis A virus expresses a single proteolytic activity which cleaves itself and all other gene products out of the single polyprotein which results from translation. Effective proteinase inhibitors of the enzymatic activity of the 3C proteinase prevent viral replication and have potential as antiviral drugs. The structure of the native 3C proteinase forms the basis for a long term project, aimed at understanding the catalytic mechanism and proteolytic specificity of the hepatitis A virus proteinase and with the ultimate goal of designing effective proteinase inhibitors with a potential as antiviral therapeutics.